RESUMO
The current studies entail quality by design (QbD)-enabled development of a simple, rapid, precise, accurate, and cost-effective high-performance liquid chromatographic method for estimation of metformin hydrochloride (M-HCl). Design of experiments (DoE) was applied for multivariate optimization of the experimental conditions of the HPLC method. Risk assessment was performed to identify the critical method parameters (CMPs) using Ishikawa diagram. The factor screening studies were performed using a two-factor three-levels design. Two independent factors, buffer pH and mobile phase composition, were used to design mathematical models. Central composite design (CCD) was used to study the response surface methodology and to study in depth the effects of these independent factors, thus evaluating the critical analytical attributes (CAAs), namely, retention time, peak area, and symmetry factor as the parameters of method robustness. Desirability function was used to simultaneously optimize the CAAs. The optimized and predicted data from contour diagram consisted of 0.02 M acetate buffer pH = 3/methanol in a ratio of 70/30 (v/v) as the mobile phase with a flow rate 1 mL/min. The separation was made on a Thermoscientific ODS HypersylTM chromatographic column (250 × 4.6 mm, 5 µm) with oven temperature 35 °C and UV detection at 235 nm. The optimized assay conditions were validated according to ICH guidelines. Hence, the results clearly showed that QbD approach could be successfully applied to optimize HPLC method for estimation of M-HCl. The method was applied both for the evaluation of M-HCl content in tablets, and for in vitro dissolution studies of M-HCl from conventional and prolonged-release tablets.
RESUMO
Smart polymeric micelles (PMs) are of practical interest as nanocarriers for the encapsulation and controlled release of hydrophobic drugs. Two hydrophobic drugs, naturally-based curcumin (Cur) and synthetic 5-fluorouracil (5-FU), were loaded into the PMs formed by a well-defined pH-sensitive poly(2-vinyl pyridine)-b-poly(ethylene oxide) (P2VP90-b-PEO398) block copolymer. The influence of the drug loading on the micellar sizes was investigated by dynamic light scattering (DLS) and it appears that the size of the PMs increases from around 60 to 100 nm when Cur is loaded. On the contrary, the loading of the 5-FU has a smaller effect on the micellar sizes. This difference can be attributed to higher molar mass of Cur with respect to 5-FU but also to higher loading efficiency of Cur, 6.4%, compared to that of 5-FU, 5.8%. In vitro drug release was studied at pH 2, 6.8, and 7.4, and it was observed that the pH controls the release of both drugs. At pH 2, where the P2VP sequences from the "frozen-in" micellar core are protonated, the drug release efficiencies exceed 90%. Moreover, it was demonstrated, by in vitro assays, that these PMs are hemocompatible and biocompatible. Furthermore, the PMs protect the Cur against the photo-degradation, whereas the non-ionic PEO corona limits the adsorption of bovine serum albumin (BSA) protein on the surface. This study demonstrates that these pH-sensitive PMs are suitable for practical utilization as human-safe and smart, injectable drug delivery systems.
